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Role of Oxidative Stress in Alcoholic/Non-Alcoholic Liver Diseases

  • Keisuke HinoEmail author
Chapter

Abstract

Oxidative stress is the shift in the balance between oxidants and antioxidants in favor of oxidants. Reactive oxygen species (ROS) play a central role in inducing oxidative stress. Mitochondria are the main site of cellular ROS production, and simultaneously have a well-organized antioxidant system. Therefore, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria is present to meet the demands of the cell. The liver also is the major iron storage organ in the body and therefore mild to moderate degrees of hepatic iron accumulation are sometimes involved in chronic liver diseases. Iron overload, especially excess divalent iron can be highly toxic, mainly via the Fenton reaction producing hydroxyl radicals. The liver is often a target of injury by oxidative stress. Oxidative stress has been shown to be present in alcoholic liver diseases, non-alcoholic steatohepatitis, and chronic hepatitis C to a greater degree than in other inflammatory liver diseases. This chapter highlights iron overload in the liver and mitochondrial ROS production through reduced mitochondrial quality control as important causative factors for inducing oxidative stress in chronic liver diseases, especially focusing on alcoholic liver disease, non-alcoholic steatohepatitis, and chronic hepatitis C.

Keywords

Reactive oxygen species Iron Mitochondria Mitochondria quality control Non-alcoholic steatohepatitis Chronic hepatitis C 

References

  1. 1.
    McCord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000;108:652–9.CrossRefGoogle Scholar
  2. 2.
    Mittler R. Oxidative stress, antioxidants and stress tolerance. Trends Plant Sci. 2002;7:505–10.CrossRefGoogle Scholar
  3. 3.
    Sha L, Tan HY, Wang N, et al. The role of oxidative stress and antioxidants in liver disease. Int J Mol Sci. 2015;16:26087–124.CrossRefGoogle Scholar
  4. 4.
    Itoh K, Igarashi K, Hayashi N, et al. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol. 1995;15:4184–93.CrossRefGoogle Scholar
  5. 5.
    Kobayashi A, Kang MI, Okawa H, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proreosomal degradation of Nrf2. Mol Cell Biol. 2004;24:7130–9.CrossRefGoogle Scholar
  6. 6.
    Kobayashi A, kang MI, Watai Y, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006;26:221–9.CrossRefGoogle Scholar
  7. 7.
    Wakabayashi N, Itoh K, Wakabayashi J, et al. keap1-null mutation leads to postnatal lethality due to constitutive NRf2 activation. Nat Genet. 2003;35:238–45.CrossRefGoogle Scholar
  8. 8.
    Peterson DR. Alcohol, iron-associated oxidative stress, and cancer. Alcohol. 2005;35:243–9.CrossRefGoogle Scholar
  9. 9.
    George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114:311–8.CrossRefGoogle Scholar
  10. 10.
    Sumida Y, Nakashima T, Yoh T, et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol. 2003;38:32–8.CrossRefGoogle Scholar
  11. 11.
    Farinati F, Cardin R, De Maria N, et al. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol. 1995;22:449–56.CrossRefGoogle Scholar
  12. 12.
    di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR. Measurements of iron status in patients with chronic hepatitis. Gastroenterology. 1992;102:2108–13.CrossRefGoogle Scholar
  13. 13.
    Fenton HJH. Oxidation of tartaric acid in presence of iron. J Chem Soc. 1894;65:899–910.CrossRefGoogle Scholar
  14. 14.
    Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4.CrossRefGoogle Scholar
  15. 15.
    Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.CrossRefGoogle Scholar
  16. 16.
    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–8.CrossRefGoogle Scholar
  17. 17.
    Harrison-Findik DD, Schafer D, Klein E, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006;281:22974–82.CrossRefGoogle Scholar
  18. 18.
    Tavill AS, Qadri AM. Alcohol and iron. Semin Liver Dis. 2004;24:317–25.CrossRefGoogle Scholar
  19. 19.
    Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53:448–57.CrossRefGoogle Scholar
  20. 20.
    Imeryuz N, Tahan V, Sonsuz A, et al. Iron preloading aggravates nutritional steatohepatitis in rats by increasing apoptotic cell death. J Hepatol. 2007;47:851–9.CrossRefGoogle Scholar
  21. 21.
    Nelson JE, Bhattacharya R, Lindor KD, et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology. 2007;46:723–9.CrossRefGoogle Scholar
  22. 22.
    Smith BW, Adams LA. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat Rev Endocrinol. 2011;7:456–65.CrossRefGoogle Scholar
  23. 23.
    Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009;50:351–7.CrossRefGoogle Scholar
  24. 24.
    Yanagitani A, Yamada S, Yasui S, et al. Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice. Hepatology. 2004;40:366–75.CrossRefGoogle Scholar
  25. 25.
    Tsuchiya H, Akechi Y, Ikeda R, et al. Suppressive effects of retinoids on iron-induced oxidative stress in the liver. Gastroenterology. 2009;136:341–350 e8.CrossRefGoogle Scholar
  26. 26.
    Otogawa K, Kinoshita K, Fujii H, et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol. 2007;170:967–80.CrossRefGoogle Scholar
  27. 27.
    Hoki T, Miyanishi K, Tanaka S, et al. Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology. 2015;62:751–61.CrossRefGoogle Scholar
  28. 28.
    Aigner E, Theurl I, Haufe H, et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology. 2008;135:680–8.CrossRefGoogle Scholar
  29. 29.
    Tapryal N, Mukhopadhyay C, Das D, Fox PL, Mukhopadhyay CK. Reactive oxygen species regulate ceruloplasmin by a novel mRNA decay mechanism involving its 3′-untranslated region: implications in neurodegenerative diseases. J Biol Chem. 2009;284:1873–83.CrossRefGoogle Scholar
  30. 30.
    Rouault TA, Gordeuk V, Anderson G. The central role of the liver in iron storage and regulation of systemic iron homeostasis. In: Arias IM, et al., editors. The liver: biology and pathobiology. 5th ed. Hoboken: Wiley-Blackwell; 2009. p. 235–50.CrossRefGoogle Scholar
  31. 31.
    Hino K, Harada M. Metal metabolism and liver. In: Ohira H, editor. The liver in systemic diseases. Heidelberg: Springer; 2016. p. 123–33.CrossRefGoogle Scholar
  32. 32.
    Aigner E, Theurl I, Theurl M, et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr. 2008;87:1374–83.CrossRefGoogle Scholar
  33. 33.
    Hofer H, Osterreicher C, Jessner W, et al. Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C. J Hepatol. 2004;40:1018–22.CrossRefGoogle Scholar
  34. 34.
    Rulyak SJ, Eng SC, Patel K, McHutchison JG, Gordon SC, Kowdley KV. Relationships between hepatic iron content and virologic response in chronic hepatitis C patients treated with interferon and ribavirin. Am J Gastroenterol. 2005;100:332–7.CrossRefGoogle Scholar
  35. 35.
    Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology. 2003;124:1509–23.CrossRefGoogle Scholar
  36. 36.
    Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med. 2007;13:97–104.CrossRefGoogle Scholar
  37. 37.
    Girelli D, Pasino M, Goodnough JB, et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol. 2009;51:845–52.CrossRefGoogle Scholar
  38. 38.
    Nishina S, Hino K, Korenaga M, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134:226–38.CrossRefGoogle Scholar
  39. 39.
    Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132:294–300.CrossRefGoogle Scholar
  40. 40.
    Migita K, Abiru S, Maeda Y, et al. Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection. Hum Immunol. 2006;67:27–32.CrossRefGoogle Scholar
  41. 41.
    Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab. 2012;23:142–53.CrossRefGoogle Scholar
  42. 42.
    Williams JA, Ding WX. A mechanistic review of mitophagy and its role in protection against alcoholic liver disease. Biomol Ther. 2015;5:2619–42.Google Scholar
  43. 43.
    Abdelmegeed MA, Ha SK, Choi Y, Akbar M, Song BJ. Role of CYP2E1 in mitochondrial dysfunction and hepatic tissue injury in alcoholic and non-alcoholic diseases. Curr Mol Pharmacol. 2017;10:207–25.CrossRefGoogle Scholar
  44. 44.
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted vis lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.CrossRefGoogle Scholar
  45. 45.
    Lambert JE. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–35.CrossRefGoogle Scholar
  46. 46.
    Peterson RE, Kalavalapalli S, Williams CM, et al. Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity. Am J Physiol Endocrinol Metab. 2016;310:E484–94.CrossRefGoogle Scholar
  47. 47.
    Satapati S, Sunny NE, Kucejova E, et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resitance and fatty liver. J Lipid Res. 2012;53:1081–92.CrossRefGoogle Scholar
  48. 48.
    Sunny NE, Bril F, Cusi K. Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endoclinol Metab. 2017;28:250–60.CrossRefGoogle Scholar
  49. 49.
    Satapati S, Kucejova B, Duarte JA, et al. Mitochondrial metabolism mediates oxidative stress in inflammation in fatty liver. J Clin Invest. 2015;125:4447–62.CrossRefGoogle Scholar
  50. 50.
    Schwer B, Ren S, Pietschmann T, et al. Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J Virol. 2004;78:7958–68.CrossRefGoogle Scholar
  51. 51.
    Korenaga M, Wang T, Li Y, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem. 2005;280:37481–8.CrossRefGoogle Scholar
  52. 52.
    Tsutsumi T, Matsuda M, Aizaki H, et al. Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology. 2009;50:378–86.CrossRefGoogle Scholar
  53. 53.
    Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J. 2007;21:2474–85.CrossRefGoogle Scholar
  54. 54.
    Piccoli C, Scrima R, Quarato G, et al. Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress. Hepatology. 2007;46:58–65.CrossRefGoogle Scholar
  55. 55.
    Pickles S, Vigie P, Youle R. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28:R170–85.CrossRefGoogle Scholar
  56. 56.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.CrossRefGoogle Scholar
  57. 57.
    Madrigal-Matute J, Cuevro AM. Regulation of liver metabolism by autophagy. Gastroenterology. 2016;150:328–39.CrossRefGoogle Scholar
  58. 58.
    Maher P. Redox control of neural function: background, mechanisms, and significance. Antioxid Redox Signal. 2006;8:1941–70.CrossRefGoogle Scholar
  59. 59.
    Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology. 2008;46:1054–61.CrossRefGoogle Scholar
  60. 60.
    Hara Y, Yanatori I, Ikeda M, et al. Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin in the context of mitochondrial depolarization. Am J Pathol. 2014;184:3026–39.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Hepatology and PancreatologyKawasaki Medical SchoolKurashikiJapan

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